Project summary: My current research is focused on understanding mechanisms by which breast cancer initiates and progresses. While many studies on breast cancer progression are focused on cancer cell biology, we are evaluating breast cancer as a systemic disease that influences the function of multiple organs. Breast cancer- associated deaths are not simply due to metastasis of cancer cells to distant organs or resistance to treatment but also due to its deleterious effects of cancer on bone and skeletal muscle. Unlike lung and pancreatic cancers where cancer leads to debilitating weight loss and clinical appearance of cachexia, physical appearance of most breast cancer patients remains ?normal?. However, loss of skeletal muscle mass without overt loss of body weight is very common and this loss of muscle mass is associated with poor outcome. In our VA funded study, we are molecularly dissecting cancer-associated skeletal muscle changes, developing biomarkers of skeletal muscle changes for early detection of cancer-induced systemic effects, and therapeutic modalities to limit the effects of cancer on skeletal muscle. These studies are extended to other cancers including bladder, lung, pancreatic, and head and neck cancers. We observed specific molecular differences in skeletal muscle of men and women with the same type of cancers. Thus, there are sex-dependent differences in cancer progression pathways, which are being explored to develop therapies that may be applicable to men with cancer. Since 11% of patients treated at VA are cancer survivors, our studies have important implications in improving health care at VA. Additional studies in the laboratory are on 1) mechanisms associated with breast cancer metastasis and therapeutic resistance; 2) genetic ancestry-dependent variability in the normal breast biology; 3) defining cell-of-origin of breast cancer using single cell genomics, 4) the impact of exposure to extraphysiologic oxygen on normal and cancer stem cells; and 5) developing chemoprevention strategies by understanding earliest events in breast cancer initiation. These studies have no overlap with VA-funded studies and funded by independent agencies. Goals of these ongoing efforts are to comprehensively understand breast cancer development and progression and to further contribute to individualizing breast cancer characterization and treatment. We aim to develop methods to classify breast cancer based on cell-of-origin and explore therapeutic modalities based on genomic aberrations. Our study on the effects of extraphysiologic oxygen is expected to change the method of tissue collection for biomarker discovery. The laboratory has been very productive over the years with 29 publications since 2015 including two recent co-author publications in prestigious journals Nature and Nature Communications and several senior author publications in journals such as Cancer Research. Our publications have received more than 15,100 citations with H-factor of 62. The institutional infrastructure, both at IU and VA, and collaborations within and outside the institution and continuous extramural funding for the past 23 years enabled us to achieve these goals. In addition to research, I have been involved in mentoring junior faculty, post-doctoral fellows, graduate students, medical students, high school students, and high school teacher summer research for the past 23 years (>50 mentees). I served/serve in various grant review committees at national and international levels and serve as an editor of prestigious journals such as Cancer Research. Since 2015, I have given 37 invited lectures at national and international venues highlighting the significance and recognition of our research.